Abstract

Human African Trypanosomiasis (HAT) is a parasitic disease that occurs in a chronic form caused by Trypanosoma brucei gambiense in Western and Central Africa, and an acute form caused by Trypanosoma brucei rhodesiense in Eastern and Southern Africa. The treatment of HAT is unsatisfactory; for over 50 years melarsoprol (Arsobal®) has been the only drug active against both forms of the disease and the only drug available to treat second stage T.b. rhodesiense infections. However, its use is hampered by high toxicity and lengthy and complicated treatment schedules. Melarsoprol therapy was substantially improved by the introduction of an abridged 10‐day melarsoprol schedule in T.b. gambiense affected areas in 2003. The new schedule was based on pharmacological investigations and was shown to be non‐inferior compared to the standard regimens in the framework of the clinical trial programs IMPAMEL I & II (1997‐2004). A significant reduction in overall hospitalization time from about 25 – 35 days to 13 days and a more economic use of the drug made it favorable to the patients and the health system. Subsequently, the conduct of the IMPAMEL III program in T.b. rhodesiense affected areas was declared a high priority by the WHO. The presented thesis aimed at a) the assessment of the safety and efficacy of the 10‐day melarsoprol schedule in T.b. rhodesiense patients and b) the rationalization of the suramin pretreatment prior to melarsoprol which is proposed to control adverse drug reactions, but which is only partially implemented in East Africa. The IMPAMEL III program consisted of the sequential conduct of a proof‐of‐concept trial and a utilization study using historic controls as comparator. The trials were conducted in two treatment centers in Tanzania and Uganda. Consenting patients with confirmed second stage T.b. rhodesiense HAT and a minimum age of 6 years were eligible for participation. Pregnant as well as unconscious or moribund patients were excluded from the trial. The primary outcome measures were safety and efficacy at end of treatment. The secondary outcome measure was efficacy during follow‐up after 3, 6 and 12 months. The studies were approved by the ethics committees in Tanzania (National Institute for Medical Research/NIMR) and Uganda (Ministry of Health) and the ethics committee of both cantons of Basel (EKBB), Switzerland. In the proof‐of‐concept trial a total of 60 patients were enrolled into two consecutive subgroups (2x15 in each center) of which only the first subgroup received the suramin pre‐treatment. Suramin as well as steroids were administered according centre‐specific guidelines. In this trial, the incidence of the encephalopathic syndrome (ES) was significantly higher in Uganda (20%) than in Tanzania (3.3%, p=0.0444). Adverse events were more frequent in patients that received suramin (63.3%) than in patients that were directly treated with melarsoprol (23.3%, p=0.0018). Based on these results, the utilization study was designed as an extension to the arm of the proofof‐ concept trial without suramin. An additional 77 patients were enrolled and directly treated with melarsoprol. Final data analysis was performed on the pooled data set of all patients that were directly treated with the 10‐day melarsoprol schedule (i.e. without suramin, n=107). These results were compared to historic controls of patients treated during past two years in the same centers. The incidence of ES in the trial population was 11.2% (CI 5‐17%) and 13% (CI 9‐17%) in the historic data. The respective case fatality rates were 8.4% (CI 3‐13.8%) and 9.3% (CI 6‐12.6%). The historic data did not allow any elucidation of the efficacy of the standard treatment regimens since systematic follow‐up of patients was not routine. However, the efficacy of the 10‐day melarsoprol schedule was highly satisfactory: all patients were free of parasites the day after treatment. 99% of the patients eligible for follow‐up were considered clinically cured 6 months after discharge. The 12 months follow up is currently ongoing. Based on the follow‐up results of the proof‐of‐concept trial no issues regarding treatment efficacy are expected. Our results show that T.b. rhodesiense patients treated with the 10‐day melarsoprol schedule were not subject to a higher incidence of serious adverse events (ES or death) than the historic controls treated with the national regimens. The hospitalization time was reduced from an average of 29 days to 13 days (p<0.0001). In a separate analysis we compared the clinical presentation of the disease in Ugandan and Tanzanian patients as a wide spectrum of disease severity has been described for T.b. rhodesiense HAT. In an ancillary study, the molecular characterization of the trypanosomes confirmed that all patients were infected with T.b. rhodesiense. The fear of an overlap in the T.b. gambiense and T.b. rhodesiense disease distribution areas could not be confirmed in our study area. On the basis of our trial experience we were able to write a review on clinical research in resource limited settings. Minimal standards for sponsors and host countries were suggested in order to ensure a trial conduct in compliance with international standards.